Introduction

Thiophene and its derivatives have attracted attention due to their wide pharmaceutical and biological activities such as antioxidant, antimicrobial, antihypertensive, antiosteoporosis, anti-inflammatory, antipsychotic, and anticonvulsant. 1 They can also act as HIV inhibitors, glucosidase inhibitors, potential JNK2 and JNK3 kinase inhibitors, adenosine agonists, and mimics of penicillins.2

Additionally, these heterocycles were reported as key building blocks of compounds with photochromic properties. 3 Therefore, numerous efficient routes have been introduced for the synthesis of thiophene derivatives. Among these methods, the use of 1,4-dithiane-2,5-diol as sulfanylacetaldehyde synthon has received extensive attention.

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K 2 CO 3 -catalyzed reactions

The reaction between 1,4-dithiane-2,5-diol (1) and α-azido vinyl ketones 2 catalyzed by K2CO3 in DMF gave 3,5-disubstituted 4-aminothiophene-2-carbaldehydes 3 in moderate to high yields.4

Kumar et al. described the synthesis of 3-nitrothiophen-2-amines 5 via the reaction of 1,4-dithiane-2,5-diol (1) and 1-(methylsulfanyl)-2-nitroethenamines 4 in the presence of K2CO3 in refluxing EtOH.5

Kumara et al. reported another K2CO3-catalyzed reaction of compound 1 and α-oxoketene dithioacetals 6 in boiling EtOH for the preparation of 2-(methylsulfanyl)thiophenes 7 in moderate to good yields.6

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Seyed Sajad Sajadikhah was born in 1982 in Mamasani, Iran. He obtained his BSc in Pure Chemistry from the University of Isfahan, MSc and PhD in Organic Chemistry under supervision of Prof. M. T. Maghsoodlou from the University of Sistan and Baluchestan, Zahedan. Currently he is a faculty member of the Department of Chemistry at the Payame Noor University, Iran. His research focuses on the heterocyclic chemistry, catalysts, and organic synthesis.

Malek Taher Maghsoodlou was born in 1955 in Gorgan, Iran. He got his BSc in Pure Chemistry from the Razi University of Kermanshah, MSc in Organic Chemistry from the Tabriz University and PhD in Organic Chemistry from the Tarbiat Modares University. Currently Prof. M. T. Maghsoodlou is a faculty member of the Department of Chemistry at the University of Sistan and Baluchestan, Zahedan, Iran. His research interests include organic synthesis, heterocyclic chemistry, organophosphorus compounds, and dynamic NMR.

Cyclopropane-based reactions

An efficient two-step method was developed for the synthesis of tetrasubstituted thiophenes 10 in the reaction of 1,4-dithiane-2,5-diol (1) with trans-2-aroyl-3-arylcyclopropane-1,1-dicarboxylates 8. It involves the [3+3] annulation of cyclopropane 8 with in situ generated sulfanylacetaldehyde in the presence of AlCl3, followed by DBUinduced rearrangement of the resulting tetrahydrothiopyranol 9, producing final products 10.7

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Selvi et al. reported one-pot sequential synthesis of disubstituted thiophenes 14. First, nitrocyclopropanedicarboxylate 11 is treated with BF3·Et2O resulting in aroylmethylidene malonate 12. Next, the mixture of 1,4-dithiane-2,5-diol 1 and triethylamine (to generate sulfanylacetaldehyde in situ) is added to compound 12 to give tetrahydrothiophenes 13, which are converted to thiophenes 14 in the presence of p-toluenesulfonic acid in satisfactory yields.8

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DABCO-catalyzed reactions

The [3+2] annulations and aromatization sequence between 1,4-dithiane-2,5-diol (1) and β'-acetoxy allenoates 15 in the presence of DABCO and Na2CO3 gave highly functionalized thiophene-2-carbaldehydes 16.9 Another effective route for the synthesis of tetrasubstituted thiophenes 18 was developed in 2016 via DABCO-catalyzed reaction of 1,3-enynes 17 and 1,4-dithiane-2,5-diol (1) at room temperature.10

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Heterocyclization of alkynones

Shi et al. developed an efficient strategy for the preparation of 2-substituted thiophene-3-carbaldehydes 20 (R2 = H) through [3+2] cycloaddition of compound 1 and ynals 19 (R2 = H).11 In a different recently reported method, 2,3-disubstituted thiophene derivatives 20 were synthesized via the reaction of similar starting materials in DMF in the presence of Et3N followed by treatment with silica gel or HCl in 70–91% overall yields.12

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Tandem Michael – intramolecular Henry reaction

Recently, Southern et al. described a new approach for the construction of 2-substituted 3-nitrothiophenes 22 by the reaction of 1,4-dithiane-2,5-diol (1) and nitroalkenes 21. First, in the presence of Et3N as a result of tandem Michael – intramolecular Henry reaction, tetrahydrothiophene is formed. Subsequent microwave irradiation under solventfree conditions gives the desired 3-nitrothiophenes 22.13

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Gewald reaction

The Gewald reaction between 1,4-dithiane-2,5-diol (1) and activated nitriles 23 was recently carried out using a reusable fiber catalyst (P-PANF) in refluxing EtOH to produce 2-aminothiophenes 24 in good to excellent yields.14

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Fused and polycyclic structures

One-pot [3+2] annulation reaction of 1,4-dithiane-2,5-diol (1) and N-substituted 1H-pyrrole-2,5-diones 25 gave a series of 2,3-thienoimides 26. The reaction was performed in the presence of Et3N followed by a subsequent dehydration and aromatization.15

Novel type of polycyclic thiophene-2-carbaldehydes 29 was synthesized via a metal-free cascade reaction of compound 1 and cyclic β-halo-α,β-unsaturated aldehydes 27 using a polymer-supported organic base 28 in EtOAc at 70°C. Base 28 was recycled up to 4 times without significant yield decrease.16

Bugge et al. demonstrated a practical and scalable four-step synthesis of 6-bromo-4-chlorothieno[2,3-d]pyrimidine 32 in 49% overall yield. The reaction steps include Gewald reaction giving thiophene 31, then pyrimidone formation, bromination, and chlorination.17

Rashmi et al. reported a multistep method for transformation of the Gewald reaction product thiophene 34 to 5,6-unsubstituted thieno[2,3-d]pyrimidines 35 in good yields. The obtained products 35 were tested for growth inhibition of Mycobacterium tuberculosis H37Rv, showing good antimycobacterial activity.18

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